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This Article Abstract Full Text (PDF) All Versions of this Article: 90/2/163    most recent expphysiol.2004.029025v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johns, E. J Search for Related Content PubMed PubMed Citation Articles by Johns, E. J Related Collections Symposia Papers Cardiovascular control

¹ Department of Physiology, University College Cork, Ireland

Abstract

The kidney plays a central role in ensuring cardiovascular homeostasis, in that it functions to ensure that the variation in fluid intake is matched to that lost through normal everyday metabolism. The autonomic nervous system, via the renal sympathetic nerves, allows kidney function to be adjusted dynamically in response to changes in sensory information arising from the cardiovascular system, the soma, viscera and the higher cortical centres. At the level of the kidney, the sympathetic nerves innervate the vascular and tubular components, thereby regulating renal haemodynamics and fluid reabsorption. The processing of sensory information by the central nervous system involves nuclei associated with cardiovascular control and it is these nuclei which are influenced by angiotensin II generated locally in the brain. The angiotensin II appears to act in a neuromodulatory fashion or as a neurotransmitter. There is now sound evidence that the baroreflex control of sympathetic outflow to the kidney, at least, is under tonic inhibitory control by brain angiotensin II, which also facilitates the impact of the somatosensory system in mediating sympatho-excitation. The significance of brain angiotensin II in mediating reflex activation of the sympathetic nerves from other sensory systems has not yet been defined and needs to be resolved. Interestingly, it may be that deficits in the production of brain angiotensin II at these nuclei could contribute in part to the genesis of hypertension.

(Received 3 November 2004; accepted after revision 9 December 2004; first published online 16 December 2004)
Corresponding author E. J. Johns: Sir Bertram Windle Building, University College Cork, College Road, Cork, Ireland. Email: e.j.johns{at}ucc.i.e

There is now a growing appreciation that over the long term there is a close relationship between the handling of fluid by the kidney and the level at which blood pressure is set (Guyton, 1992). The degree to which the fluid filtered at the kidney is reabsorbed by the tubules is importantly influenced by two major extrinsic control mechanisms, hormones circulating in the plasma (e.g. aldosterone and angiotensin) and the renal sympathetic innervation. Clearly, any deficit in the control exerted by these systems will eventually determine whether a hypertensive level of blood pressure ensues, which will eventually lead to increased damage to the renal vascular and tubular structures (Swales et al. 1995). In such individuals there is increased risk of cardiovascular accidents, such as stroke and myocardial infarcts, as well as progressive damage to the kidney leading to end-stage renal disease. It therefore becomes important to understand and appreciate the mechanisms which underly these relationships both normally and in pathophysiological states.

Pressure–natriuresis relationship

There is a general acknowledgement that there is a linear relationship between the blood pressure at the kidney and the degree to which sodium is excreted, thus, as pressure increases, sodium excretion rises. Experimental evidence, summarized by Granger (1992), would suggest that as renal perfusion pressure rises, there is transmission of this increased pressure into the renal interstitium at the interlobar, arcuate and, to an extent, the interlobular arteries. The increase in renal interstitial hydrostatic pressure will, via the increase in Starling forces at the peritubular capillaries in the cortex, act against the isosmotic fluid reabsorption at the proximal tubule, resulting in an increase in sodium and water excretion. It is important to highlight the fact that as renal perfusion pressure rises, at least in the range 80–180 mmHg, there is autoregulation of both renal blood flow (RBF) and glomerular filtration rate (GFR), and so glomerular filtration pressure, but this control is exerted by the afferent and efferent resistance arterioles, i.e. downstream from the larger vessels (interlobular and arcuate arteries), which contribute less to the autoregulatory capacity of the kidney.

One of the outcomes of this pressure–natriuresis relationship is that it places sodium reabsorption by the proximal tubule at the centre of the ability of the kidney to determine long-term extracellular fluid volume and cardiovascular homeostasis (see Fig. 1). Moreover, this means that any humoral or neural influences which act on the proximal tubular reabsorptive processes will reset the overall renal handling of the fluid load to a higher or lower level (Doris, 2000). Two important examples which can potentially act in this way are circulating angiotensin II and the renal sympathetic nerves (see Fig. 1). The control exerted by these mechanisms probably occurs in a rapid and dynamic manner, allowing the animal/individual to excrete a sodium load rapidly (for example in a postprandial state). Conversely, should the neural or humoral control be blunted for any reason, for example in pathophysiological states, then there may be a deficit of the ability to excrete a sodium load, leading to a stressing of the cardiovascular system which may ultimately contribute to a chronically raised blood pressure.

View larger version (17K): [in this window] [in a new window]   Figure 1 Relationship between blood pressure and proximal tubular sodium reabsorption and the extra-renal control exerted by circulating angiotensin II and the sympathetic innervation of the kidney.

The renal sympathetic nerves

The kidney has a dense sympathetic innervation with preganglionic fibres arising from T11 to L3, with some variation depending on individuals (DiBona, 2000). In the rat, approximately 2000 fibres enter the kidney at the hilus and, as with all autonomic fibres, they trail across both vascular and tubular structures. Associated with the varicosities, neuroeffector junctions have been described at vascular smooth muscle cells of both the afferent and efferent arterioles, as well as at most tubular segments in the cortex, proximal tubule, loop of Henle and distal tubule (Barajas et al. 1992). At a functional level, there is a large body of evidence demonstrating that the renal nerves can act at the afferent and efferent resistance arterioles to determine both RBF and GFR. At the renin-containing cells of the afferent arteriole they stimulate renin release, while at the tubules they stimulate fluid reabsorption by the epithelial cells (DiBona & Kopp, 1997). However, the impact of the renal nerves on those different functionalities occurs at different levels of activity within the renal nerves. This is illustrated in Table 1, which shows that at low levels of direct electrical stimulation of the renal nerves there is a significant increase in renin release, but no other renal functional change. At higher levels of stimulation, renin secretion is further raised but there is a concommitant decrease in sodium excretion, reflecting a raised tubular reabsorption (Wu & Johns, 2004), and this occurs at a time when there are no measurable changes in renal haemodynamics. It is only at the highest rate of renal nerve stimulation that there are reductions in RBF and GFR, but again, this takes place at a time when renin secretion is raised even higher and the reduction in sodium excretion is much greater (Hesse & Johns, 1984).

Reflex regulation of renal sympathetic nerve activity

The amount of nerve traffic passing along the renal nerves arises from a number of reflexes, which determine sympathetic outflow. These are shown in Fig. 2. There is good evidence that stimulation of the somatosensory system, that is sensory nerve fibres arising from the skin and muscles, can increase renal sympathetic nerve activity (Hirooka & Dampney, 1995), which means that during everyday activity, this system has a continuous input into the areas of the brain involved with autonomic control. The cardiovascular baroreceptors probably have one of the most important inputs. They include the high pressure receptors of the carotid sinus and the aortic arch, and if blood pressure falls at these sites there is a reflex increase in sympathetic nerve activity to the kidney (Carlsson et al. 1992). The low pressure receptors are found primarily in the cardiopulmonary areas and are sensitive to the volume of fluid in the cardiovascular system. Thus, an increase in volume within the vascular system will stimulate the cardiopulmonary receptors, resulting in a reflex inhibition of renal sympathetic nerve activity, thereby mobilizing fluid (DiBona & Sawin, 1985). It is pertinent to point out that there are chemo- and mechanoreceptors in the viscera, that is the gut (Weaver et al. 1987) and liver (Morita et al. 1991; Hevener et al. 2001), and the kidneys (Kopp, 1992) which form the basis of the reno-renal reflex, and when activated can stimulate the sympathetic nervous system. Finally, there is a major input from the higher cortical centres, where signals from the environment, e.g. visual and auditory systems, can cause a major increase in sympathetic outflow. Thus, the hypothalamic centres receive a wide range of sensory signals, all of which have to be integrated to ensure appropriate changes in sympathetic nerve traffic to the kidney and so the functional responses.

View larger version (14K): [in this window] [in a new window]   Figure 2 Afferent inputs to the central nervous system which contribute to the reflex regulation of renal sympathetic nerve activity.

Evidence from a range of studies has accrued, which has given rise to the proposal that besides the renal renin–angiotensin system, which generates circulating angiotensin II, a number of other ‘local’ renin–angiotensin systems may exist within different tissues and organs. One of these appears to be within the brain, where there are reports that all the components exist to allow the generation of angiotensin II at extracellular sites (Wright & Harding, 1997). Interestingly, the content of angiotensinogen in the brain is quite high, being 30% that found in the liver (Lynch et al. 1986). Moreover, mRNA for angiotensinogen is found almost exclusively in the astrocytes (Stornetta et al. 1988), suggesting that the peptide must be present in high amounts in the interstitial fluid in the brain. It raises the interesting question as to how the angiotensin II may be formed locally, whether there is neuronal uptake of angiotensinogen by nerve cells which metabolize it intracellularly to generate angiotensin II, or whether there is extracellular generation of angiotensin II which is then taken up by the nerve cells.

Converting enzyme has been found in the brain and appears to be primarily located in the microvessels, but presently it is unclear whether the enzyme is active within the nerve cells themselves. Indeed, the possibility arises that other peptidases may be available within the neurones which can act upon angiotensinogen to produce the active peptide, angiotensin II. The situation regarding renin is also uncertain, in that the mRNA for the renin gene is diffusely distributed throughout the brain with little indication of sites of localized production (Wright & Harding, 1997). The issue then arises as to how closely involved renin may be in the metabolism of angiotensinogen or whether there are other enzymes available which could act on the substrate to generate the active peptide.

A number of reports have shown that the angiotensin II receptors are distributed widely in the brain (Allen et al. 1998), both of the AT-1 and AT-2 subtypes. Immunochemical studies have shown that the nuclei involved with cardiovascular control have a relatively high density of angiotensin receptors; these include the nucleus tractus solitarius (NTS), area postrema, rostral and caudal venterolateral medulla. It is also important to note that a high density of receptors also exists in the subfornical organs, where the blood–brain barrier is leaky, and it is likely that it is these receptors that are primarily sensitive to and activated by circulating angiotensin II rather than that generated locally (McKinley et al. 1996).

The mechanism whereby angiotensin II produced locally in the brain exerts its action remains a focus of study. It may act as a neuromodulator, whereby it may modify the rate of transmission across synapses, in a way analogous to that demonstrated in the periphery (Handa & Johns, 1985). Alternatively, since the peptide has been found within the nerve cells themselves (Wright & Harding, 1997), it may be released as a neurotransmitter, but evidence for this view has yet to be produced in a convincing way.

Brain angiotensin and renal sympathetic nerve activity

The role of brain angiotensin II in modulating the reflex control of sympathetic nerve traffic has been a source of investigation for some time. Two major reflexes have received attention, namely the high pressure baroreceptors and the somatosensory system.

Baroreflex regulation of renal sympathetic nerve activity.  There has been on-going interest in the role of angiotensin II in modulating baroreflex control of sympathetic outflow (renal sympathetic nerve activity has been used widely as an example) and of heart rate, which reflects regulation exerted by both sympathetic and parasympathetic nerves on heart rate. In our own studies (Johns, 2002), we examined baroreflex control of renal nerve activity and heart rate by administering the vasopressor phenylephrine and the vasodepressor nitroprusside and generating baroreflex curves using the Kent algorithm (Kent et al. 1972). The importance of angiotensin II receptors in the brain was determined by blocking AT-1 receptors using intracerebroventricular (I.C.V.) losartan, or by raising the level of angiotensin II by exogenous I.C.V. infusion.

Studies were undertaken in the chloralose-/urethane-anaesthetized rat and it was found that blockade of the brain renin–angiotensin system, with either an AT-1 receptor antagonist or a converting enzyme inhibitor, increased the sensitivity of the baroreflex relationship, whereas it was decreased by I.C.V. infusion of angiotensin II. Taken together, these observations supported the view that angiotensin II exerted a tonic inhibitory action on the baroreflex regulation of renal sympathetic nerve activity. At the same time, the baroreflex control of heart rate was measured, but neither the blocking drugs nor I.C.V. angiotensin II had any effect on the slope of the relationship. This view was supported by studies using conscious chronically instrumented rats, and it was also found that angiotensin II exerted a tonic inhibitory action on the sensitivity of the baroreflex control of renal sympathetic nerve activity, but again, was without influence on baroreflex control of the heart rate. These observations would suggest that angiotensin II was less important in the reflex neural regulation of the heart. Together, these findings indicate that angiotensin II exerts a modulatory role on the neural connections in the brain that are involved in the baroreflex control of sympathetic outflow. Great effort has been applied to establishing where angiotensin II might be involved and the peptide can clearly change activity of the neurones in the NTS (Hirooka & Dampney, 1995), RVLM (Saigusa et al. 2003) and caudal venterolateral medulla (CVLM) (Potts et al. 2000). However, exactly how the action of the peptide at these sites comes together to decrease the sensitivity of the baroreflex has yet to be fully elucidated.

Somatosensory regulation of renal sympathetic nerve activity.  A second significant area where angiotensin II within the brain exerts an influence is in determining the magnitude of the renal sympatho-excitation in response to activation of the somatosensory system. In chloralose-/urethane-anaesthetized rats, the somatosensory system was activated by giving subcutaneous injections of capsaicin, which elicited increases in blood pressure and heart rate. Under these conditions, there was a reflex increase in renal sympathetic nerve activity (Zhang et al. 1997) and when renal perfusion pressure was maintained at an unchanged level so that neither RBF nor GFR were altered, there were reversible decreases in urine flow and sodium excretion. Importantly, these antidiuretic and antinatriuretic responses did not occur if the kidneys had been denervated at the beginning of the study (Huang & Johns, 1998). The role of brain angiotensin II in this reflex was investigated in two ways: first, by giving blockers I.C.V.; and second, by infusing angiotensin II I.C.V. It was found that when either losartan or captopril was given I.C.V., then the antidiuretic and antinatriuretic responses were blunted, or prevented, whereas if angiotensin II was given together with captopril I.C.V., then the renal excretory responses to somatosensory stimulation were restored (Huang & Johns, 2000). Together, these pieces of evidence clearly demonstrated that in order for sensory information arising from afferent sensory neurones in the periphery to cause an increase in renal sympathetic nerve activity, angiotensin II had to be present with the brain. What is not clear at present is at which particular nuclei the angiotensin II is exerting this effect. The NTS, where the somatosensory system has been shown to have an important input, is a possibility, but whether other areas are involved remains to be determined.

Summary

In summary, the neural control of the kidney has a major role in determining cardiovascular homeostasis by determining the extent of fluid reabsorption. The renal sympathetic nerves act to stimulate proximal tubular fluid reabsorption, and reflexly regulated increases and decreases in sympathetic traffic to the kidney are important in dealing with changes in sodium intake both acutely and chronically. Almost all systems of the body send afferent information into the brain, the cardiovascular, somatosensory and visceral systems, where it is integrated to ensure that an appropriate level of sympathetic nerve traffic passes to the kidney. Importantly, within the brain, locally generated angiotensin II, acting as either a neurotransmitter or a neuromodulator, can influence many of the different systems and change the balance in the impact made by the input from the various sensory systems. Exactly how this integration occurs within the brain is unclear and requires further investigation.

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Acknowledgements

This work has been generously supported by the British Heart Foundation and I am indebted to all research students and fellows who have helped develop these thoughts. My particular thanks to Dr Chunlong Huang who has been central to much of this work.

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/2/163    most recent expphysiol.2004.029025v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johns, E. J Search for Related Content PubMed PubMed Citation Articles by Johns, E. J Related Collections Symposia Papers Cardiovascular control